Sickle cell disease is an autosomal recessive disorder and the most common genetic disease affecting African-Americans. Approximately 0.15% of African-Americans are homozygous for sickle cell disease, and 8% have sickle cell trait. Hemoglobin S polymerization leads to red cell rigidity, microvascular obstruction, inflammation, and end-organ ischemia-reperfusion injury and infarction. Up to 50% of sickle cell patients have endothelial dysfunction due to impaired bioavailability of endogenous nitric oxide (NO) due in large part to scavenging of nitric oxide by cell-free plasma hemoglobin. These data suggest that therapies directed at restoring NO bioavailability might prove beneficial. Between 8 and 20% of patients with sickle cell disease develop painful, disfiguring, and indolent leg ulcers, but higher rates of more than 50% have been reported (Serjeant, Arch Intern Med 133:690-694, 1974; Akinyanju and Akinsete, Trop Geogr Med 31:87-91, 1979). The ulcers usually appear between the ages of 10 and 50 years and have been reported to be more frequent in males than in females in some studies. The etiology of leg ulcers is unclear. Trauma, infection, severe anemia, and warmer temperature predispose to ulcer formation. Decreased blood flow after the ulcer has healed often results in recurrence. One study reported that 37% of sickle cell anemia (SCA) patients suffering from pulmonary hypertension also have leg ulcers (De Castro et al., Am J Hematol 83:19-25, 2008). Therefore, there has been an association between leg ulcers and pulmonary hypertension as complications more common in the hemolytic phenotype. Current treatment options for leg ulcerations, including antibiotics, compression bandages, dressing changes, Unna boot compression dressing, silver and zinc oxide gauze, and maggot therapy tend to rely on stimulation of granulation formation in the wound. Pathological changes in the microcirculation associated with ulceration are not addressed.
Nitric oxide mediates essential biological processes, including vasodilatation, antimicrobial activity and wound healing (Fang, J Clin Invest 99:2818-2825, 1997; Bulgrin et al., Wounds 7:48-57, 1995; Kirk et al., Surgery 114:155-159, 1993). NO is manufactured on epithelial surfaces, such as the mouth and stomach, and on the skin surface in humans by sequential reduction of nitrate and nitrite. This relies on the synthesis of nitrite by the bacterial reduction of inorganic nitrate present in saliva or sweat.